Blood GFAP protein levels may help in early FAP diagnosis
GFAP marks preclinical stage, while elevated NfL corresponds to symptom onset
A protein called glial fibrillary acidic protein (GFAP) is found at higher levels in the blood of people with familial amyloid polyneuropathy (FAP), even before symptoms appear, relative to healthy people, a study finds.
Also, blood levels of a protein called neurofilament light chain (NfL) were elevated only in those who already show FAP symptoms. This contrasts with previous studies that found elevated NfL before the disease manifested.
“This suggests that [blood GFAP] elevation marks the disease from its preclinical stages, while [blood NfL] increase corresponds with the presence of neurological manifestations,” the study’s researchers wrote. The study, “Elevated serum concentrations of GFAP in hereditary transthyretin amyloidosis since pre-symptomatic stages,” was published in the Journal of Neurology by researchers in Italy.
FAP, also called hereditary transthyretin amyloidosis with polyneuropathy, is caused by mutations in the TTR gene that lead to a faulty version of the transthyretin protein being produced that forms clumps that build up to toxic levels in the nerves that branch out from the brain and spinal cord, leading to neurological damage. While the first symptoms may not appear until late in adulthood, an early FAP diagnosis may allow treatment to begin when it’s likely to be most effective.
Differences in protein levels
“Identifying reliable biomarkers for [FAP] is critical for early diagnosing, monitoring disease progression, and assessing the effectiveness of currently available therapies,” wrote the researchers, who evaluated blood levels of GFAP and NfL as possible biomarkers of FAP. GFAP is a marker of damage to astrocytes, the star-shaped cells that support neurons in the brain, while NfL is a marker of nerve fiber damage.
The study included 111 people (median age, 64) who carried genetic mutations known to cause FAP and 183 healthy people who served as controls. Among the mutation carriers, 56 had symptoms (symptomatic) and 55 were presymptomatic. All the mutation carriers were recruited from Italian reference centers. More than half (52.3%) had the most common FAP-causing mutation, known as Val30Met.
The researchers found that blood GFAP levels were significantly higher in both symptomatic and presymptomatic patients relative to the healthy controls. Specifically, GFAP levels were more than three times higher in symptomatic patients (238.4 picograms per milliliter [pg/mL]) and 1.4 times higher in presymptomatic patients (105.5 pg/mL) than controls (75.5 pg/mL). There were no significant differences between symptomatic and presymptomatic patients.
“To the best of our knowledge, this study is the first to document significantly elevated [blood GFAP] levels in both [symptomatic FAP] patients and pre-symptomatic subjects,” the researchers wrote.
NfL blood levels were about six times higher in symptomatic patients than healthy controls (43.7 vs. 7.5 pg/mL), but presymptomatic patients had NfL levels similar to those of controls (9.4 vs. 7.5 pg/mL), suggesting NfL increases only when the disease begins to manifest.
Healthy female controls had significantly higher GFAP levels than their male counterparts. While a similar trend was found in the two patient groups, the differences didn’t reach statistical significance, however. There were no significant sex-related differences in GFAP or NfL levels in symptomatic and presymptomatic patients.
Higher GFAP and NfL levels were each significantly associated with more severe nerve damage, as assessed with the Neuropathy Impairment Score (NIS), suggesting both may serve as biomarkers for tracking how the disease is progressing. The findings suggest GFAP “marks the disease from its preclinical stages,” while elevated NfL “corresponds with the presence of neurological manifestations,” the researchers wrote. This means NfL levels may not only mark the shift toward manifesting symptoms, but also serve as a biomarker of disease progression.
Future studies that follow patients over time “are needed to further characterize how these biomarker concentrations evolve throughout disease progression and in response to specific treatments,” the researchers wrote.
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